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Mechanism and prevention of lipopolysaccharide-induced early pregnancy complications

脂多糖诱发早孕并发症的机制及预防

基本信息

批准号：
10445230
负责人：
Bibhash Chandra Paria
金额：
$ 41.85万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445230
关键词：
Alkaline Phosphatase Anti-Bacterial Agents Anti-Inflammatory Agents Antibodies Bacteria Bacterial Infections Bacterial Toxins CD14 Antigen CD14 gene Cell Surface Proteins Cell surface Cells Clinical Coculture Techniques Complex Coupled Cytokine Gene Decidua Decidual Cell Defect Dendritic Cells Development Drug Metabolic Detoxication Drug usage Economics Embryo Endotoxins Epithelial Escherichia coli Female Fetal health Genes Hematopoietic Homeostasis IL6 gene Impairment Infection Infectious Agent Inflammation Inflammatory Injections Interleukin-1 beta Isoenzymes Late pregnancy Lipid A Lipopolysaccharides Maternal Health Mediating Medical Modeling Mothers Mus Neutrophil Infiltration Neutrophilic Infiltrate Placenta Population Positioning Attribute Pregnancy Pregnancy Complications Pregnancy Maintenance Premature Birth Prevention Production Psyche structure Publications Publishing Recombinants Research Role Signal Pathway Signal Transduction Site Source Spontaneous abortion Supplementation TLR4 gene TNF gene Technology Testing Therapeutic Tissues Uterus Virulence Factors adverse pregnancy outcome cell type chemokine combat cytokine early pregnancy early pregnancy loss experimental study improved insight migration natural Blastocyst Implantation neutrophil novel novel strategies pathogen preclinical study prenatal recruit response social stillbirth success tool

项目摘要

PROJECT SUMMARY The available evidence suggests that intrauterine and/or maternal bacterial infection is a major cause of early and late pregnancy complications. Current antibacterial and anti-inflammatory drugs used to treat bacterial infection during pregnancy are considered harmful to maternal and fetal health. Thus, continued research to look for better treatment options to avoid bacterial infection-induced pregnancy complications is alluring. The decidua and placenta are uniquely positioned at the maternal-embryonic interface to serve as a first line of defense against bacterial toxins, but their defensive mechanisms against bacterial toxins are poorly understood. Lipopolysaccharide (LPS) is an endotoxin of Gram-negative E. coli that is associated with infection-induced pregnancy defects. LPS recognition by cell surface proteins is an important step required for the initiation of its inflammatory signaling or inactivation by cell surface molecules. Our preliminary results establish that: 1) the uterine luminal epithelium, decidua and placenta express the LPS sensing and signaling TLR4/CD14/MD2 complex; 2) LPS injection on day 5 of pregnancy terminates pregnancy by day 8 via selective-activation of the MyD88-dependent TLR4 signaling pathway at the embryo implantation site (EIS); 3) LPS induces expression of proinflammatory cytokine genes such as Tnf-α & Il-1β, chemokine genes such as Cxcl1&2, and neutrophil recruitment to the EIS; 4) cell surfaces of the decidua and placenta express tissue- nonspecific alkaline phosphatase (TNAP) isozyme that is capable of dephosphorylating LPS; 5) dephosphorylated LPS is non-inflammatory and non-toxic to murine pregnancy; and 6) AP isozyme treatment alleviates LPS-induced early pregnancy loss in mice. These preliminary findings have led to the hypothesis that LPS-induced microenvironment disruption at the early EIS is a result of concerted action of resident decidual cells and recruited neutrophils, and LPS detoxification by supplementation and/or induction of TNAP production/activity may abrogate LPS-mediated early pregnancy defects/loss. To test our hypothesis, we have proposed three mechanistic aims. In Aim 1, we will use Cre-lox and antibody- mediated neutralization technologies to establish that an important step in the development of LPS-induced unwanted inflammation at the early EIS is decidual cell-type-dependent recruitment of inflammatory neutrophils. In Aim 2, we will generate novel female mice with uterine deletion of TNAP gene Alpl to determine whether endogenous TNAP deficiency in the uterus augments the response to LPS. In Aim 3, we will examine the potential of TNAP and its activator or inducer in mitigating LPS- or E. coli-induced early pregnancy defects/loss. Upon completion of these aims, we hope to gain: 1) insights into the mechanisms of infection-induced inflammation at the early EIS; and 2) develop a novel LPS-detoxification therapeutic strategy to avoid bacteria- induced early pregnancy complications.

项目摘要现有证据表明，宫内和/或母体细菌感染是早期妊娠的主要原因。和晚期妊娠并发症。目前用于治疗细菌感染的抗菌和抗炎药物怀孕期间感染被认为对母亲和胎儿健康有害。因此，继续研究，寻找更好的治疗方案，以避免细菌感染引起的妊娠并发症是诱人的。蜕膜和胎盘独特地位于母胚界面，作为第一道屏障，防御细菌毒素，但他们对细菌毒素的防御机制很差明白脂多糖（LPS）是革兰氏阴性大肠杆菌的内毒素。大肠杆菌，感染导致的妊娠缺陷细胞表面蛋白对LPS的识别是细胞免疫所需的重要步骤。炎症信号的启动或细胞表面分子的失活。我们的初步结果确定：1）子宫腔上皮、蜕膜和胎盘表达LPS传感和信号传导 TLR 4/CD 14/MD 2复合物; 2）在妊娠第5天注射LPS通过以下方式终止妊娠：在胚胎着床部位（EIS）选择性激活MyD 88依赖性TLR 4信号通路; 3） LPS诱导促炎细胞因子基因如TNF-α和IL-1β、趋化因子基因如 Cxcl 1和2，以及中性粒细胞募集到EIS; 4）蜕膜和胎盘的细胞表面表达组织- 能够使LPS去磷酸化的非特异性碱性磷酸酶（TNAP）同工酶; 5）去磷酸化LPS对小鼠妊娠是非炎性和无毒的;和6）AP同工酶处理抑制LPS诱导的小鼠早期妊娠丢失。这些初步发现导致了一种假设 LPS诱导的微环境破坏在早期EIS是协调行动的结果，常驻蜕膜细胞和募集的中性粒细胞，以及通过补充和/或 TNAP产生/活性的诱导可以消除LPS介导的早期妊娠缺陷/丧失。为了验证我们的假设，我们提出了三个机械目标。在目标1中，我们将使用Cre-lox和抗体- 介导的中和技术，以建立一个重要的一步，在发展中的LPS诱导在早期EIS的不必要的炎症是蜕膜细胞类型依赖性的炎性细胞聚集，中性粒细胞在目标2中，我们将产生具有TNAP基因Alpl的子宫缺失的新雌性小鼠，以确定子宫内内源性TNAP缺乏是否增强了对LPS的反应。在目标3中，我们将研究 TNAP及其激活剂或诱导剂在减轻LPS-或E.大肠杆菌致早孕缺陷/损失。在完成这些目标后，我们希望获得：1）深入了解感染诱导的机制，在早期EIS的炎症;和2）开发一种新的LPS解毒治疗策略，以避免细菌- 导致早期妊娠并发症。